Steroid esters

ABSTRACT

Compounds of the general formula (I), ##STR1## in which formula the 1,2-position is saturated or is a double bond, R 1  is hydrogen or a straight or branched hydrocarbon chain, R 2  is hydrogen or a straight or branched hydrocarbon chain, R 3  is acyl, X 1  is hydrogen or halogen, X 2  is hydrogen or halogen and provided that 1) R 1  and R 2  are not simultaneously hydrogen, 2) X 1  and X 2  are not simultaneously hydrogen, 3) when the 1,2-position is a double bond, R 1  and R 2  are not simultaneously methyl groups, 4) when the 1,2-position is a double, R 1  is a hydrogen atom and R 2  is a straight or branched hydrocarbon chain having 1-10 carbon atoms R 3  is acyl having 11-20 carbon atoms, processes for their preparation, pharmaceutical preparations containing them and the use of the compounds in the treatment of inflammatory and allergic conditions.

FIELD OF INVENTION

The present invention relates to novel anti-inflammatory andanti-allergic active compounds and to processes for their preparation.The invention also relates to pharmaceutical compositions containing thecompounds and to methods of the pharmacological use of the composition.

The object of the invention is to provide an anti-inflammatory,immunosuppressive and anti-allergic glucocorticosteroid or apharmaceutical composition thereof with high activity at the applicationplace, e.g. in the respiratory tract, on the skin, in the intestinaltract, in the joints or in the eye, directing the drug to delimitedtarget area, thereby inducing low glucocorticoid systemic effects.

A further object of the invention is to provide a pharmaceuticalcomposition containing liposomes including a pharmacologically activesteroid fatty acid ester of the invention in order to improve drugdelivery and to minimize side effects of the therapy.

BACKGROUND ART

Glucocorticosteroids (GCS) are the most valuable drugs for relief ofasthma and rhinitis. It is widely accepted that GCS exert theirtherapeutic efficacy by anti-inflammatory and anti-anaphylactic actionswithin airway and lung tissue. The long term oral use of GCS is greatlyhampered by severe side effects outside the lung region. Accordingly,only a minor part of patients with asthma or rhinitis currently undergooral GCS therapy. A better safety can be reached by delivering GCS byinhalation. However, also the potent inhaled GCS in current wideclinical use--beclomethasone 17α,21-dipropionate and budesonide--have arather narrow safety margin and for both unwanted GCS actions within thegeneral circulation have been reported with the highest of therecommended doses for inhalation.

Liposomes are membrane-like vesicles consisting of series of concentriclipid bilayers alternating with hydrophilic compartments. Liposomes havebeen used as carriers for different kinds of pharmaceutically activecompounds in order to improve drug delivery and to minimize side effectsof the therapy.

Glucocorticosteroids are incorporated into liposomes only at a lowconcentration and are poorly retained in the vesicles. Esterification ofGCS in 21-position with fatty acids increases the degree ofincorporation and the retention of the steroid in the vesicles. It hasbeen shown that the fatty acid chain acts as a hydrophobic "anchor"which holds the steroid nucleus in the hydrated polar head groups of thephospholipid and thereby improves the interaction between theglucocorticosteroid and the liposome.

Liposome-encapsulated glucocorticosteroids for therapeutic use have beendescribed (M. De Silva et al., Lancet 8130 (1979), 1320) and U.S. Pat.No. 4,693,999 describes liposomal formulations of glucocorticosteroidsfor inhalation.

DISCLOSURE OF THE INVENTION

One object of the present invention is to provide new GCS compounds. Thenew compounds are characterized by anti-inflammatory, immunosuppressivand anti-anaphylactic potency at the application site and particularlythey have a markedly improved relationship between that potency and theactivity to provoke GCS actions outside the treated region. Thepreferred mode of administration of the new compounds is by inhalationwhen the application site is within the airways.

Another object of the invention is to provide an anti-inflammatory andanti-allergic pharmaceutical composition containing steroid esterliposomes for local administration primarily to the respiratory tract.Such a composition provides for an improvement of the therapeuticproperties of the steroid ester by a prolongation of the local retentionin the airways and a direction of the drug to specific target cells.

The compounds of the invention are characterized by the formula ##STR2##or a stereoisomeric component thereof, in which formula the 1,2-positionis saturated or is a double bond,

R₁ is hydrogen or a straight or branched hydrocarbon chain having 1-4carbon atoms,

R₂ is hydrogen or a straight or branched hydrocarbon chain having 1-10carbon atoms,

R₃ is a acyl having a straight or branched, saturated or unsaturatedhydrocarbon chain having 1-20 carbon atoms,

X₁ is hydrogen or halogen

X₂ is hydrogen or halogen and provided that

1) R₁ and R₂ are not simultaneously hydrogen,

2) X₁ and X₂ are not simultaneously hydrogen,

3) when the 1,2-position is a double bond, R₁ and R₂ are notsimultaneously methyl groups,

4) when the 1,2-position is a double bond, R₁ is a hydrogen atom and R₂is a straight or branched hydrocarbon chain having 1-10 carbon atoms R₃is acyl having 11-20 carbon atoms.

The acyl is derived from

CH₃ COOH: acetic acid;

C₂ H₅ COOH: propionic acid;

C₃ H₇ COOH: butyric acid;

C₄ H₉ COOH: valeric acid;

C₅ H₁₁ COOH: hexanoic acid;

C₆ H₁₃ COOH: heptanoic acid;

C₇ H₁₅ COOH: octanoic acid;

C₈ H₁₇ COOH: nonanoic acid;

C₉ H₁₉ COOH: decanoic acid;

C₁₀ H₁₉ COOH: capric acid;

C₁₁ H₂₃ COOH: lauric acid;

C₁₂ H₂₅ COOH: tridecanoic acid;

C₁₃ H₂₇ COOH: myristic acid;

C₁₄ H₂₉ COOH: pentadecanoic acid;

C₁₅ H₃₁ COOH: palmitic acid;

C₁₆ H₃₃ COOH: heptadecanoic acid;

C₁₇ H₃₅ COOH: stearic acid;

C₁₇ H₃₃ COOH: oleic acid;

C₁₇ H₃₁ COOH: linolic acid;

C₁₇ H₂₉ COOH: linolenic acid;

C₁₈ H₃₇ COOH: nonadecanoic acid;

C₁₉ H₃₉ COOH: icosanoic acid.

The preferred acylgroups are derived from

C₁₁ H₂₃ COOH: lauric acid;

C₁₃ H₂₇ COOH: myristic acid;

C₁₅ H₃₁ COOH: palmitic acid;

C₁₇ H₃₅ COOH: stearic acid;

C₁₇ H₃₃ COOH: oleic acid;

C₁₇ H₃₁ COOH: linolic acid;

C₁₇ H₂₉ COOH: linolenic acid,

and particularly it is palmitic acid.

A straight or branched hydrocarbon chain having 1-4 carbon atoms ispreferably an alkyl group having 1-4 carbon atoms, particularly a methylgroup.

A straight or branched hydrocarbon chain having 1-10 carbon atoms ispreferably an alkyl group having 1-10 carbon atoms and preferably 1-4carbon atoms, particularly a methyl or a propyl group.

A halogen atom in this specification is fluorine, chlorine or bromine.The preferred halogen atom is fluorine.

The preferred compounds of the invention are those where in formula I

the 1,2-position is saturated,

R₁ is hydrogen or a straight or branched hydrocarbon chain having 1-4carbon atoms,

R₂ is a hydrogen or a straight or branched hydrocarbon chain having 1-10carbon atoms,

R₃ is acyl having a straight or branched, saturated or unsaturatedhydrocarbon chain having 1-20 carbon atoms,

X₁ is hydrogen or halogen,

X₂ is hydrogen or halogen, and

provided that

1) R₁ and R₂ are not simultaneously hydrogen and

2) X₁ and X₂ are not simultaneously hydrogen.

Particularly preferred compounds of the invention are those where informula I

the 1,2-position is saturated

R₁ is a hydrogen atom

R₂ is a propyl group

R₃ is acyl having 11-20 carbon atoms

X₁ is fluorine

X₂ is fluorine.

A further preferred compound of the invention is the one of the formulaI wherein

the 1,2-position is a double bond,

R₁ is a hydrogen atom,

R₂ is a propyl group,

R₃ is a palmitoyl group,

X₁ is fluorine,

X₂ is fluorine.

The most preferred compound of the invention has the formula ##STR3##

The preferred embodiment of the invention is a composition containingthe preferred compound of the invention in combination with liposomes.

At instances where an object of the invention is to provide apharmaceutical composition containing liposomes the active compound ofthe composition should be a compound of the formula I wherein R₃ is acylhaving 11-20 carbon atoms.

At instances where an object of the invention is to provide apharmaceutical composition without liposomes, the active compound of thecomposition should be a compound of the formula I wherein R₃ is acylhaving 1-10 carbon atoms, preferably 5-10 carbon atoms.

The individual stereoisomeric components present in a mixture of asteroid having the above formula (I) can be elucidated in the followingway due to the chirality at the carbon atom in 22-position and withrespect to the R₂ substituent: ##STR4##

The preferred stereoisomeric component has the 22R configuration.

Methods of preparation

The steroid esters, ##STR5## wherein St is ##STR6## and X₁, X₂, R₁, R₂have the meanings given above, R₄ is a straight or branched, saturatedor unsaturated alkyl group with 1-19 carbon atoms and the 1,2-positionis saturated or is a double bond, are prepared by any of the followingalternative methods.

A. Reaction of a compound of the formula

    St--OH

wherein St has the definition given above, with a compound of theformula ##STR7## wherein R₄ has the definition given above.

The esterification of the 21-hydroxy compound may be effected in knownmanner, e.g. by reacting the parent 21-hydroxy steroid with theappropriate carboxylic acid, advantageously in the presence oftrifluoroacetic anhydride and preferably in the presence of an acidcatalyst, e.g. p-toluenesulfonic acid.

The reaction is advantageously performed in an organic solvent such asbenzene or methylene chloride; the reaction being conveniently performedat a temperature of 20°-100° C.

B. Reaction of a compound of the formula

    St--OH

wherein St has the definition given above, with a compound of theformula ##STR8## wherein R₄ has the definition given above, and X is ahalogen atom, such as chlorine, bromine, iodine and fluorine, or thegroup ##STR9## wherein R₄ has the definition given above.

The parent 21-hydroxy compound may be treated with the appropriatecarboxylic acid halide or anhydride, preferably in a solvent such ashalogenated hydrocarbons, e.g. methylene chloride or ethers, e.g.dioxane in the presence of a base such as triethylamine or pyridine,preferably at low temperature, e.g. -5° C. to +30° C.

C. Reaction of a compound of the formula

    St--Y

wherein St has the definition given above and Y is selected fromhalogen, e.g. Cl, Br and I, or from mesylate or p-toluenesulfonate, witha compound of the formula ##STR10## wherein R₄ has the definition givenabove and A ⊕ is a cation.

A salt of the appropriate carboxylic acid with an alkali metal, e.g.lithium, sodium or potassium, or a triethyl ammonium or tributylammoniumsalt may be reacted with the appropriate alkylating agent of the formulaSt--Y. The reaction is performed preferably in a polar solvent such asacetone, methylethyl ketone, dimethyl formamide or dimethyl sulfoxide,conveniently at a temperature in the range 25°-100° C.

In any of methods A-C a final reaction step in order to resolve anepimeric mixture into its components may be necessary in case a pureepimer is desired.

Pharmaceutical preparations

The compounds of the invention may be used for different modes of localadministration dependent on the site of inflammation, e.g.percutaneously, parenterally or for local administration in therespiratory tract by inhalation. An important aim of the formulationdesign is to reach optimal bioavailability of the active steroidingredient. For percutaneous formulations this is advantagenouslyachieved if the steroid is dissolved with a high thermodynamic activityin the vehicle. This is attained by using a suitable system or solventscomprising suitable glycols, such as propylene glycol or 1,3-butandioleither as such or in combination with water.

It is also possible to dissolve the steroid either completely orpartially in a lipophilic phase with the aid of a surfactant as asolubilizer. The percutaneous compositions can be an ointment, an oil inwater cream, a water in oil cream or a lotion. In the emulsion vehiclesthe system comprising the dissolved active component can make up thedisperse phase as well as the continuous one. The steroid can also existin the above compositions as a micronized, solid substance.

Pressurized aerosols for steroids are intended for oral or nasalinhalation. The aerosol system is designed in such a way that eachdelivered dose contains 10-1000 μg, preferably 20-250 μg of the activesteroid. The most active steroids are administered in the lower part ofthe dose range. The micronized steroid consists of particlessubstantially smaller than 5 μm, which are suspended in a propellentmixture with the assistance of a dispersant, such as sorbitan trioleate,oleic acid, lecithin or sodium salt of dioctylsulphosuccinic acid.

The steroid can also be administered by means of a dry powder inhaler.

One possibility is to mix the micronized steroid with a carriersubstance such as lactose or glucose. The powder mixture is dispensedinto hard gelatin capsules, each containing the desired dose of thesteroid. The capsule is then placed in a powder inhaler and the dose isinhaled into the patient's airways.

Another possibility is to process the micronized powder into sphereswhich break up during the dosing procedure. This spheronized powder isfilled into the drug reservoir in a multidose inhaler, e.g. Turbuhaler.A dosing unit meters the desired dose which is then inhaled by thepatient. With this system the steroid with or without a carriersubstance is delivered to the patient.

The steroid can also be included in formulations intended for treatinginflammatory bowel diseases, either by the oral route or rectally.Formulations for the oral route should be constructed so that thesteroid is delivered to the inflamed parts of the bowel. This can beaccomplished by different combinations of enteric and/or slow or controlrelease principles. For the rectal route an enema type formulation issuitable.

Preparation of liposome compositions

The lecithins used in this invention have fatty acid chains of differentlengths and therefore have different phase-transition temperatures.Examples of lecithins used are those derived from egg and soybean andsynthetic lecithins like dimyristoyl phosphatidylcholine (DMPC),dipalmitoyl phosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC). By manipulation of the structure lecithinsstable carriers with variable biodegradable properties could beformulated. This would enable one to prolong the release of theentrapped steroid ester.

The extent of the interaction of the steroid ester with e.g. dipalmitoylphosphatidylcholine (DPPC) vesicles is dependent on the ester chainlength with increased interaction observed as the chain lengthens.

The inclusion of cholesterol or cholesterol derivatives in liposomeformulations has become very common due to its properties in increasingliposome stability.

The initial stages of the preparation of liposomes according to thepresent invention may conveniently follow procedures described in theliterature, i.e. the components being dissolved in a solvent, e.g.ethanol or chloroform which is then evaporated. The resulting lipidlayer is then dispersed in the selected aqueous medium whereafter thesolution is either shaken or sonicated. The liposomes of this inventionpreferably have a diameter of between 0.1 and 10 μm.

In addition to the main liposome-forming lipid(s) which is usuallyphospholipid, other lipids (e.g. cholesterol or cholesterol stearate) inthe amount of 0-40% w/w of the total lipids may be included to modifythe structure of the liposome membrane. In optimizing the uptake of theliposome a third component providing a negative charge (e.g. dipalmitoylphosphatidyl glycerol) or a positive charge (e.g. stearylamine acetateor cetylpyridinium chloride) may be incorporated.

A wide range of proportions of steroid ester to lipid during formationmay be used depending on the lipid and the conditions used. Drying,(freeze-drying or spray drying) of the liposomes in the presence oflactose can be used with a lactose content in the range of 0 to 95% ofthe final composition.

The composition according to the invention which is particularlypreferred contains liposomes and(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.The routes of administration involves powder aerosols, instillation,nebulization and pressurized aerosols.

WORKING EXAMPLES

The invention will be further illustrated by the followingnon-limitative examples. In the examples a flow-rate of 2.5 ml/cm².h⁻¹is used at the preparative chromatographic runs. Molecular weights arein all examples determined with chemical ionization mass spectrometry(CH₄ as reagent gas) and the melting points on a Leitz Wetzlar hot stagemicroscope. The HPLC analyses (High Performance Liquid Chromatography)have been performed on a μBondapak C₁₈ column (300×3.9 mm i.d.) with aflow rate of 1.0 ml/min and with ethanol/water in ratios between 40:60and 60:40 as mobile phase, if not otherwise stated.

Example 1(22R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.

A solution of palmitoyl chloride (1.2 g) in 10 ml of dioxane was addeddrop-wise to a solution of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione(200 mg) in 25 ml of pyridine. The reaction mixture was stirred for 16 hat room temperature. Methylene chloride (150 ml) was added and thesolution washed with 1M hydrochloric acid, 5% aqueous potassiumcarbonate and water and dried. The crude product after evaporation waspurified by chromatography on a Sephadex LH-20 column (87×2.5 cm) usingchloroform as mobile phase. The fraction 210-255 ml was collected andevaporated leaving 203 mg of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.Melting point 87°-90° C.; molecular weight 706 (calc. 707.0). Purity:96% (HPLC-analysis).

Example 2(22R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione

To a solution of (22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione (50 mg) and palmitoyl chloride (35mg) in 10 ml of methylene chloride was added dropwise a solution oftriethylamine (13 mg) in 2 ml of methylene chloride. The reactionmixture was stirred for 2 h at room temperature. Another 50 ml ofmethylene chloride was added and the reaction mixture was worked up asin Example 1. The crude product was purified on a Sephadex LH-20 column(85×2.5 cm) using chloroform as mobile phase. The fraction 210-250 mlwas collected and evaporated yielding 34 mg of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.Molecular weight 706 (cacl. 707.0). Purity: 95% (HPLC-analysis).

Example 3(22S)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.

A solution of palmitoyl chloride (0.4 ml) in 10 ml of dioxane was addeddrop-wise to a solution of(22S)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione(70 mg) in 25 ml of pyridine. The reaction mixture was stirred for 16 hat room temperature and worked up as in Example 1. The crude product waspurified on a Sephadex LH-20 column (87×2.5 cm) using chloroform asmobile phase. The fraction 225-265 ml was collected and evaporatedyielding 92 mg of(22S)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dioneas an oil. Molecular weight: 706 (calc. 707.0). Purity: 97%(HPLC-analysis).

Example 4(22R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-myristoyloxypregn-4-ene-3,20-dione.

Myristoyl chloride was synthesized by refluxing myristic acid (7.0 g)and thionyl chloride (9 ml) in trichloroethylene (100 ml) for 3 h. Thesolvent was then evaporated.

To a solution of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione(51 mg) in 10 ml of methylene chloride was added myristoyl chloride (32mg) followed by triethylamine (13 mg) dissolved in methylene chloride (5ml). The reaction mixture was stirred for 4 h at room temperature.Further methylene chloride was added and the mixture successively washedwith 0.1M hydrochloric acid and water (3×50 ml). after drying andevaporation the residue was purified by chromatography on MerckKieselgel 60 using heptane:acetone, 6:4, as mobile phase yielding 27 mgof(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-myristoyloxypregn-4-ene-3,20-dione.Molecular weight 678 (calc. 678.9). Purity: 96.8% (HPLC-analysis).

Example 5(22R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-lauroyloxypregn-4-ene-3,20-dione.

To a solution of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione(51 mg) in 5 ml of methylene chloride was added lauroyl chloride (28 mg)followed by triethylamine (13 mg) dissolved in 2 ml of methylenechloride. The reaction mixture was stirred at room temperature for 3 h,further methylene chloride was added and the organic phase washedsuccessively with 0.1M hydrochloric acid and water (3×30 ml). Afterdrying and evaporation the residue was purified by chromatography onMerck Kieselgel 60 using hexane/acetone, 6:4, as mobile phase. Theproduct obtained was further purified in a second chromatographic stepusing petroleum ether:ethyl acetate, 3:2, as mobile phase yielding 33 mgof(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-dihydroxy-21-lauroyloxypregn-4-ene-3,20-dione.Molecular weight 650 (calc. 650.8). Purity: 96.9% (HPLC-analysis).

Example 6(22R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.

A solution of palmitoyl chloride (2.3 ml) in 15 ml of dioxane was addeddrop-wise to a solution of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregna-1,4-diene-3,20-dione(700 mg) in 30 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (76×6.3 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction1020-1350 ml was collected and evaporated yielding 752 mg of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.Melting point 141°-145° C.; [α]_(D) ²⁵ =+71.6° (c=0.204; CH₂ Cl₂);molecular weight 704 (calc. 704.9). Purity: 97.7% (HPLC-analysis).

Example 7(22S)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.

A solution of palmitoyl chloride (0.5 ml) in 5 ml of dioxane was addeddropwise to a solution of(22S)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregna-1,4-diene-3,20-dione(150 mg) in 10 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction215-315 ml was collected and evaporated yielding 132 mg of(22S)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.Melting point 176°-180° C.; [α]_(D) ²⁵ =+47.5° (c=0.198; CH₂ Cl₂);molecular weight 704 (calc. 704.9). Purity: 99% (HPLC-analysis).

Example 8(22R)-21-Acetoxy-16α,17α-butylidenedioxy-6α,9α-difluoro-11β-hydroxy-pregn-4-ene-3,20-dione

A solution of acetyl chloride (38 mg) in 5 ml of dioxane was addeddropwise to a solution of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione(75 mg) in 5 ml of pyridine. The reaction mixture was stirred for 16 hat room temperature. After evaporation methylene chloride (75 ml) wasadded and the solution was washed with cold 5% aqueous potassiumcarbonate and saturated sodium chloride solution. The crude productafter evaporation was purified by chromatography on a Sephadex LH-20column (85×2.5 cm) using chloroform as a mobile phase. The fraction365-420 ml was collected and evaporated leaving 57 mg of(22R)-21-acetoxy-16α,17α-butylidenedioxy-6α,9α-difluoro-11β-hydroxypregn-4-ene-3,20-dione.Melting point 182°-189°; [α]_(D) ²⁵ =+112.0° (c=0.225; CH₂ Cl₂);molecular weight 510 (calc 510.6). Purity 99.0% (HPLC-analysis).

Example 9(22R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-valeroyloxypregn-4-ene-3,20-dione

A solution of valeroyl chloride (60 mg) in 5 ml of dioxane was addeddropwise to a solution of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione(75 mg) in 5 ml of pyridine. The reaction mixture was stirred for 16 hat room temperature. After evaporation methylene chloride (75 ml) wasadded and the solution was washed with cold 5% aqueous potassiumcarbonate and saturated sodium chloride solution. The crude productafter evaporation was purified by chromatography on a Sephadex LH-20column (85×2.5 cm) using chloroform as a mobile phase. The fraction265-325 ml was collected and evaporated leaving 50 mg of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-valeroyloxypregn-4-ene-3,20-dione.Melting point 181°-185°; [α]_(D) ²⁵ =+109.4° (c=0.212; CH₂ Cl₂);molecular weight 552 (calc. 552.7). Purity 99.8% (HPLC-analysis).

Example 10(22R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-capryloxypregna-1,4-diene-3,20-dione.

A solution of decanoyl chloride (0.2 ml) in 3 ml of dioxane was addeddropwise to a solution of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregna-1,4-diene-3,20-dione(100 mg) in 6 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (71×6.3 cm) using chloroform asmobile phase. The fraction 1470-1725 ml was collected and evaporatedyielding 113 mg of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-capryloxypregna-1,4-diene-3,20-dione.Melting point 182°-184° C. [α]_(D) ²⁵ =-71.5° (c=0.186; CH₂ Cl₂).Molecular weight 620 (calc. 620.9). Purity: 97.7% (HPLC-analysis).

Example 116α,9α-Difluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione

A suspension of 0.9 g of tris(triphenylphosphine)rhodium chloride in 250ml of degassed toluene was hydrogenated for 45 min at room temperatureand atmospheric pressure. A solution of 1.0 g of fluocinolone16α,17α-acetonide in 100 ml of absolute ethanol was added and thehydrogenation was continued for another 40 h. The reaction product wasevaporated and the residue purified by flash chromatography on silicausing acetone-petroleum ether as mobile phase to remove the main part ofthe catalyst. The eluate was evaporated and the residue further purifiedby chromatography on a Sephadex LH-20 column (72.5×6.3 cm) usingchloroform as mobile phase. The fraction 3555-4125 ml was collected andevaporated yielding 0.61 g of6α,9α-difluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione.Melting point 146°-151° C. [α]_(D) ²⁵ =+124.5° (c=0.220;CH₂ Cl₂).Molecular weight 454 (calc. 454.6). Purity: 98.5% (HPLC-analysis).

Example 126α,9α-Difluoro-11β-hydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]-21-palmitoyloxypregn-4-ene-3,20-dione

A solution of palmitoyl chloride (2.1 ml) in 15 ml of dioxane was addeddropwise to a solution of6α,9α-difluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione(310 mg) in 30 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. the crude productwas purified on a Sephadex LH-20 column (76×6.3 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction1035-1260 ml was collected and evaporated yielding 158 mg of6α,9α-difluoro-11β-hydroxy-16α,17α[(1-methylethylidene)bis(oxy)]-21-palmitoyloxypregn-4-ene-3,20-dione.Melting point 82°-86° C. [α]_(D) ²⁵ =+85.3° (c=0.232; CH₂ Cl₂).Molecular weight 692 (calc. 692.9). Purity: 98.6% (HPLC-analysis).

Example 13 (22R)- and(22S)-21-Acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dione

(22S)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(68 mg) was dissolved in 1 ml of pyridine. Acetic anhydride (1 ml) wasadded and the reaction mixture stirred at room temperature for 1 h,poured into ice-water and extracted with 3×25 ml of methylene chloride.The extract was dried and evaporated. The residual 22RS-mixture wasresolved by chromatography on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fractions380-400 ml (A) and 420-440 ml (B) were collected and evaporated.

After precipitation from methylene chloride--petroleum ether fraction Ayielded 14 mg of(22S)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dione.Melting point 179°-186° C. [α]_(D) ²⁵ =+86.2° (c=0.188; CH₂ Cl₂).Molecular weight 492 (calc. 492.6). Purity: 97.5% (HPLC-analysis).

Fraction B gave after precipitation 20 mg of(22R)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dione.Melting point 169°-172° C. [α]_(D) ²⁵ =+139.0° (c=0.200; CH₂ Cl₂).Molecular weight 492 (calc. 492.6). Purity: 97.9% (HPLC-analysis).

Example 14(22RS)-16α,17α-Butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.

To a suspension of 1.4 g of tris(triphenylphosphine)rhodium chloride in300 ml of toluene was added a solution of 1170 mg of6α-fluoro-11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione in 250ml of absolute ethanol. The mixture was hydrogenated 22 h at roomtemperature and atmospheric pressure and evaporated. The residue wasprecipitated from acetone-chloroform yielding 661 mg of6α-fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione. Molecularweight 396 (calc. 396.5). Purity: 96.6% (HPLC-analysis).

6α-Fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione (308 mg) wasadded in portions to a solution of butanal (115 mg) and 70% perchloricacid (0.2 ml) in 50 ml of dioxane. The reaction mixture was stirred atroom temperature for 6 h. Methylene chloride (200 ml) was added and thesolution washed with 10% aqueous potassium carbonate and water anddried. The residue after evaporation was purified on a Sephadex LH-20column (87×2.5 cm) using chloroform as mobile phase. The fraction420-500 ml was collected and evaporated yielding 248 mg of(22RS)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Melting point 85°-96° C. [α]_(D) ²⁵ =+119.8° (c=0.192; CH₂ Cl₂).Molecular weight 450 (calc. 450.6). Purity: 96.1% (HPLC-analysis). Thedistribution between the 22R- and 22S-epimers was 59/41 (HPLC-analysis).

A solution of palmitoyl chloride (0.21 ml) in 3 ml of dioxane was addeddropwise to a solution of(22RS)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(50 mg) in 6 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction185-230 ml was collected and evaporated yielding 42 mg of(22RS)-16α,17α-butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dioneas an oil. Molecular weight 688 (calc. 688.97). Purity: 99.0% and thedistribution between the 22R- and 22S-epimers was 15/85 (HPLC-analysis).

Example 15(22R)-16α,17α-Butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.

(22RS)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(225 mg) was resolved by preparative HPLC in portions on a μBondapak C₁₈column (150×19 mm) using ethanol:water, 40:60, as mobile phase. Thefractions centered at 265 ml (A) and 310 ml (B) were collected andevaporated. After precipitation from methylene chloride--petroleum etherfraction A yielded 68 mg of(22R)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Melting point 180°-192° C. [α]_(D) ²⁵ =+138.9° (c=0.144; CH₂ Cl₂).Molecular weight 450 (calc. 450.6). Purity: 99.4% (HPLC-analysis).

Fraction B gave after precipitation 62 mg of(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Melting point 168°-175° C. [α]_(D) ²⁵ =+103.7° (c=0.216; CH₂ Cl₂).Molecular weight 450 (calc. 450.6). Purity: 99.5% (HPLC-analysis).

A solution of palmitoyl chloride (0.22 ml) in 5 ml of dioxane was addeddropwise to a solution of(22R)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(32 mg) in 10 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (87×2.5 cm) using chloroform asmobile phase. The fraction 215-250 ml was collected and evaporatedyielding 38 mg of(22R)-16α,17α-butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dioneas an oil. Molecular weight 688 (calc. 688.97). Purity: 96.0%(HPLC-analysis)

Example 16(22S)-16α,17α-Butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.

(22RS)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(68 mg) was dissolved in 1 ml of pyridine. Acetic anhydride (1 ml) wasadded and the reaction mixture stirred at room temperature for 1 h,poured into ice-water and extracted with 3×25 ml of methylene chloride.The extract was dried and evaporated. The residual 22RS epimeric mixturewas resolved by chromatography on a Sephadex LH-20 column (89×2.5 cm)using heptane:chloroform:ethanol, 20:20:1, as mobile phase. Thefractions 380-400 ml (A) and 420-440 ml (B) were collected andevaporated.

After precipitation from methylene chloride--petroleum ether fraction Ayielded 14 mg of(22S)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dione.Melting point 179°-186° C. [α]_(D) ²⁵ =+86.2° (c=0.188; CH₂ Cl₂).Molecular weight 492 (calc. 492.6). Purity: 97.5% (HPLC-analysis).

Fraction B gave after precipitation 20 mg of(22R)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dione.Melting point 169°-172° C. [α]_(D) ²⁵ =+139.0° (c=0.200; CH₂ Cl₂Molecular weight 492 (calc. 492.6). Purity: 97.9% (HPLC-analysis).

To a solution of 14 mg of(22S)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dionein 2 ml of ethanol, 2 ml of 2M hydrochloric acid was added. Afterstirring at 60° C. for 5 h the reaction mixture was neutralized withsaturated aqueous sodium hydrogen carbonate and extracted with 3×25 mlof methylene chloride. The combined extracts were washed with water,dried and evaporated. The residue was purified on a Sephadex LH-20column (87×2.5 cm) using chloroform as mobile phase. The fraction455-510 ml was collected and evaporated giving 7 mg of(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β-21-dihydroxypregn-4-ene-3,20-dione.Molecular weight 450 (calc. 450.6). Purity: 96.6%.

A solution of palmitoyl chloride (195 mg) in 5 ml of dioxane was addeddropwise to a solution of(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(32 mg) in 10 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction205-245 ml was collected and evaporated yielding 37 mg of(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dioneas an oil. Molecular weight 688 (calc. 688.97). Purity: 96.4%(HPLC-analysis).

Example 17(22RS)-16α,17α-Butylidenedioxy-6α-fluoro-11β-hydroxy-21-lauroyloxypregn-4-ene-3,20-dione.

A solution of lauroyl chloride (0.4 ml) in 3 ml of dioxane was addeddropwise to a solution of(22RS)-(16α,17α)-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(50 mg) in 6 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction215-250 ml was collected and evaporated yielding 15 mg of(22RS)-16α,17α-butylidenedioxy-6α-fluoro-11β-hydroxy-21-lauroyloxypregn-4-ene-3,20-dione.Melting point 125°-143° C. [α]_(D) ²⁵ =+92.8° (c=0.208; CH₂ Cl₂).Molecular weight 632 (calc. 632.9). Purity: 96.2% (HPLC-analysis). Thedistribution between the 22R- and 22S-epimers was 58/42 (HPLC-analysis).

Example 18(22R)-16α,17α-Butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.

6α-Fluoro-11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione (400mg) was added in portions to a solution of butanal (0.18 ml) and 70%perchloric acid (0.2 ml) in 50 ml of dioxane. The reaction mixture wasstirred at room temperature for 16 h. Methylene chloride (200 ml) wasadded and the solution washed with 10% aqueous potassium carbonate andwater and dried. The residue after evaporation was purified on aSephadex LH-20 column (75×6.3 cm) using chloroform as mobile phase. Thefraction 2880-3300 ml was collected and evaporated yielding 1209 mg of(22RS)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregna-1,4-diene-3,20-dione.Molecular weight 448 (calc. 448.5). The purity was 95.7% and thedistribution between the 22R- and 22S-epimers 55/45 (HPLC-analysis).

(22RS)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregna-1,4-diene-3,20-dione(36 mg) was chromatographed on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fractions1720-1800 ml (A) and 1960-2025 ml (B) were collected and evaporated. Thetwo products were precipitated from methylene chloride--petroleum ether.The product from fraction A (12 mg) was identified with ¹ H-NMR and massspectrometry to be(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregna-1,4-diene-3,20-dioneand the product from the B fraction (10 mg) as the 22R-epimer.

The epimers had the following properties. Epimer 22S: Melting point172°-180° C.; [α]_(D) ²⁵ =+62.3° (c=0.132; CH₂ Cl₂); molecular weight448 (calc. 448.5). Epimer 22R: Melting point 95°-106° C.; [α]_(D) ²⁵=+105.9° (c=0.152; CH₂ Cl₂); molecular weight 448 (calc. 448.5). Thepurity of the epimers was determined by HPLC-analysis to be 98.9% forthe 22S-epimer and 97.7% for the 22R-epimer.

A solution of palmitoyl chloride (172 mg) in 5 ml of dioxane was addeddropwise to a solution of(22R)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregna-1,4-diene-3,20-dione(56 mg) in 10 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction225-285 ml was collected and evaporated yielding 31 mg of(22R)-16α,17α-butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.Melting point 95°-100° C. [α]_(D) ²⁵ =+68.0° (c=0.200; CH₂ Cl₂).Molecular weight 686 (calc. 686.95). Purity: 97.76% (HPLC-analysis).

Example 19(22S)-16α,17α-Butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.

A solution of palmitoyl chloride (110 mg) in 5 ml of dioxane was addeddropwise to a solution of(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregna-1,4-diene-3,20-dione(46 mg) in 10 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction185-225 ml was collected and evaporated yielding 37 mg of(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.Melting point 65°-68° C. [α]_(D) ²⁵ =+53.0° (c=0.200; CH₂ Cl₂).Molecular weight 686 (calc. 686.95). Purity: 95.9% (HPLC-analysis).

Example 206α-Fluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione.

A suspension of 2.1 g of tris(triphenylphosphine)rhodium chloride in 500ml of toluene was hydrogenated at room temperature and atmosphericpressure for 45 min, when the catalyst was in solution. A solution of2.0 g of6α-fluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dionein 1000 ml of absolute ethanol was added and the hydrogenation wascontinued for another 65 h. The reaction mixture was evaporated and theresidue purified on a Sephadex LH-20 column (71×6.3 cm) using chloroformas mobile phase. The fraction 2010-2445 ml was collected and evaporatedyielding 1.51 g of6α-fluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione.Melting point 209°-219° C. [α]_(D) ²⁵ =+133.5° (c=0.230; CH₂ Cl₂).Molecular weight 436 (calc. 436.5). Purity: 99.6% (HPLC-analysis).

Example 216α-Fluoro-11β-hydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]-21-palmitoyloxypregn-4-ene-3,20-dione.

A solution of palmitoyl chloride (0.21 mg) in 3 ml of dioxane was addeddropwise to a solution of6α-fluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]-pregn-4-ene-3,20-dionein 6 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (76×6.3 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction1035-1230 ml was collected and evaporated yielding 63 mg of6α-fluoro-11β-hydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]-21-palmitoyloxypregn-4-ene-3,20-dione.Melting point 99°-101° C. [α]_(D) ²⁵ =+89.8° (c=0.206; CH₂ Cl₂).Molecular weight 674 (calc. 674.94). Purity: 97.9% (HPLC-analysis).

Example 229α-Fluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione.

A solution of 675 mg of tris(triphenylphosphine)rhodium chloride in 250ml of toluene was hydrogenated at room temperature and atmosphericpressure for 45 min. A solution of 1 g of triamcinolone16α,17α-acetonide in 100 ml of absolute ethanol was added and thehydrogenation was continued for another 40 h. The reaction mixture wasevaporated and the main part of the catalyst removed by flashchromatography with aceton:petroleum ether (b.p. 40°-60° C.), 40:60, asmobile phase. The crude product was further purified on a Sephadex LH-20column (72.5×6.3 cm) using chloroform as mobile phase. The fraction2746-3195 ml was collected and evaporated yielding 404 mg of9α-fluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione.Melting point 238°-41° C. [α]_(D) ²⁵ =+145.2° (c=0.288; CH₂ Cl₂).Molecular weight 436 (calc. 436.5). Purity: 99% (HPLC-analysis).

Example 239α-Fluoro-11β-hydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]-21-palmitoyloxypregn-4-ene-3,20-dione.

A solution of palmitoyl chloride (0.69 mg) in 10 ml of dioxane was addeddropwise to a solution of9α-fluoro-11β,21-dihydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dionein 20 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction240-305 ml was collected and evaporated yielding 102 mg of6α-fluoro-11β-hydroxy-16α,17α-[(1-methylethylidene)bis(oxy)]-21-palmitoyloxypregn-4-ene-3,20-dioneas an oil. Molecular weight 674 (calc. 674.94). Purity: 98%(HPLC-analysis).

Example 24(22RS)-16α,17α-Butylidenedioxy-9α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.

To a solution of freshly distilled butanal (100 mg) and 0.2 ml ofperchloric acid (70%) in 50 ml of purified and dried dioxane9α-fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione (340 mg) wasadded in small portions with stirring during 20 min. The reactionmixture was stirred at room temperature for another 5 h. Methylenechloride (200 ml) was added and the solution was washed with aqueouspotassium carbonate and water and dried over anhydrous magnesiumsulfate. The crude product obtained after evaporation was purified on aSephadex LH-20 column (72.5×6.3 cm) using chloroform as mobile phase.The fraction 2760-3195 ml was collected and evaporated yielding 215 mgof(22RS)-16α,17α-butylidenedioxy-9α-fluoro-11β-21-dihydroxypregn-4-ene-3,20-dione.Molecular weight 450 (calc. 450.6). Purity: 97.4% (HPLC-analysis).

A solution of palmitoyl chloride (0.13 mg) in 2.5 ml of dioxane wasadded dropwise to a solution of(22RS)-16α,17α-butylidenedioxy-9α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(40 mg) in 5 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (87×2.5 cm) using chloroform asmobile phase. The fraction 220-300 ml was collected and evaporatedyielding 42 mg of(22RS)-16α,17α-butylidenedioxy-9α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dioneas an oil. Molecular weight 688 (calc. 688.97). The distribution betweenthe 22R- and 22S-epimers was 61/39 (HPLC-analysis).

Example 25(22R)-16α,17α-Butylidenedioxy-9α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.

(22RS)-16α,17α-Butylidenedioxy-9α-fluoro-11β-21-dihydroxypregn-4-ene-3,20-dione(200 mg) was resolved by chromatography on a Sephadex LH-20 column(76×6.3 cm) using a heptane-chloroform-ethanol (20:20:1) mixture asmobile phase. The fractions 7560-8835 ml (A) and 8836-9360 ml (B) werecollected and evaporated. The product from fraction A (128 mg) wasidentified with ¹ H-NMR and mass spectrometry to be(22RS)-16α,17α-butylidenedioxy-9α-fluoro-11β-21-dihydroxypregn-4-ene-3,20-dioneand the product from the B fraction (50 mg) as the 22R-epimer.

The epimers had the following properties. Epimer 22S: Melting point180°-190° C.; [α]_(D) ²⁵ =+105.6° (c=0.214; CH₂ Cl₂ molecular weight 450(calc. 450.6). Epimer 22R: Melting point 147°-151° C.; [α]_(D) ²⁵=+133.7° (c=0.196; CH₂ Cl₂); molecular weight 450 (calc. 450.6). Thepurity of the epimers was determined by HPLC-analysis to be 95.6% forthe 22S-epimer and 98.2% for the 22R-epimer.

A solution of palmitoyl chloride (0.34 ml) in 5 ml of dioxane was addeddropwise to a solution of(22R)-16α,17α-butylidenedioxy-9α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(50 mg) in 10 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction180-205 ml was collected and evaporated yielding 36 mg of(22R)-16α,17α-butylidenedioxy-9α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dioneas an oil. Purity: 96.3% (HPLC-analysis). Molecular weight 688 (calc.688.97).

Example 26(22S)-16α,17α-Butylidenedioxy-9α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione.

A solution of palmitoyl chloride (0.14 ml) in 15 ml of dioxane was addeddropwise to a solution of(22S)-16α,17α-butylidenedioxy-9α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(41 mg) in 3 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (89×2.5 cm) usingheptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction215-260 ml was collected and evaporated yielding 26 mg of(22S)-16α,17α-butylidenedioxy-9α-fluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dioneas an oil. Purity: 91.4% (HPLC-analysis). Molecular weight 688 (calc.688.97).

Example 27(22R)-16α,17α-Butylidenedioxy-9α-fluoro-11β-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.

A solution of palmitoyl chloride (75 mg) in 2.5 ml of dioxane was addeddropwise to a solution of(22R)-16α,17α-butylidenedioxy-9α-fluoro-11β,21-dihydroxypregna-1,4-diene-3,20-dione(25 mg) in 5 ml of pyridine. The reaction mixture was stirred at roomtemperature overnight and worked up as in Example 1. The crude productwas purified on a Sephadex LH-20 column (85×2.5 cm) using chloroform asmobile phase. The fraction 235-285 ml was collected and evaporatedyielding 27 mg of(22R)-16α,17α-butylidenedioxy-9α-fluoro-11β-hydroxy-21-palmitoyloxypregna-1,4-diene-3,20-dione.Melting point 116°-121° C.; [α]_(D) ²⁵ =+67.4° (c=0.172;CH₂ Cl₂).Molecular weight 686 (calc. 687.0). Purity: 96.5% (HPLC-analysis).

Example 28 Pharmaceutical Preparations

The following non-limitative example illustrate formulations intendedfor different topical forms of administration. The amount of activesteroid in the percutaneous formulations are ordinarily 0.001-0.2%(w/w), preferably 0.01-0.1% (w/w).

    ______________________________________                                        Formulation 1, Ointment                                                       Steroid, micronized           0.025   g                                       Liquid paraffin               10.0    g                                       White soft paraffin     ad    100.0   g                                       Formulation 2, Ointment                                                       Steroid                       0.025   g                                       Propylene glycol              5.0     g                                       Sorbitan sesquioleate         5.0     g                                       Liquid paraffin               10.0    g                                       White soft paraffin     ad    100.0   g                                       Formulation 3, Oil in water cream                                             Steroid                       0.025   g                                       Cetanol                       5.0     g                                       Glyceryl monostearate         5.0     g                                       Liquid paraffin               10.0    g                                       Cetomacrogol 1000             2.0     g                                       Citric acid                   0.1     g                                       Sodium citrate                0.2     g                                       Propylene glycol              35.0    g                                       Water                   ad    100.0   g                                       Formulation 4, Oil in water cream                                             Steroid, micronized           0.025   g                                       White soft paraffin           15.0    g                                       Liquid paraffin               5.0     g                                       Cetanol                       5.0     g                                       Sorbimacrogol stearate        2.0     g                                       Sorbitan monostearate         0.5     g                                       Sorbic acid                   0.2     g                                       Citric acid                   0.1     g                                       Sodium citrate                0.2     g                                       Water                   ad    100     g                                       Formulation 5, Water in oil cream                                             Steroid                       0.025   g                                       White soft paraffin           35.0    g                                       Liquid paraffin               5.0     g                                       Sorbitan sesquioleate         5.0     g                                       Sorbic acid                   0.2     g                                       Citric acid                   0.1     g                                       Sodium citrate                0.2     g                                       Water                   ad    100.0   g                                       Formulation 6, Lotion                                                         Steroid                       0.25    mg                                      Isopropanol                   0.5     ml                                      Carboxyvinylpolymer           3       mg                                      NaOH                          q.s.                                            Water                   ad    1.0     g                                       Formulation 7, Suspension for injection                                       Steroid, micronized           0.05-10 mg                                      Sodium carboxymethylcellulose 7       mg                                      NaCl                          7       mg                                      Polyoxyethylene (20) sorbitan 0.5     mg                                      monooleate                                                                    Phenyl carbinol               8       mg                                      Water, sterile          ad    1.0     ml                                      Formulation 8, Aerosol for oral and                                           nasal inhalation                                                              Steroid, micronized           0.1%    w/w                                     Sorbitan trioleate            0.7%    w/w                                     Trichlorofluoromethane        24.8%   w/w                                     Dichlorotetrafluoromethane    24.8%   w/w                                     Dichlorodifluoromethane       49.6%   w/w                                     Formulation 9, Solution for atomization                                       Steroid                       7.0     mg                                      Propylene glycol              5.0     g                                       Water                   ad    10.0    g                                       Formulation 10, Powder for inhalation                                         A gelatin capsule is filled with a mixture of                                 Steroid, micronized           0.1     mg                                      Lactose                       20      mg                                      The powder is inhaled by means of an                                          inhalation device.                                                            Formulation 11, Powder for inhalation                                         The spheronized powder is filled into a                                       multidose powder inhaler. Each dose contains                                  Steroid, micronized           0.1     mg                                      Formulation 12, Powder for inhalation                                         The spheronized powder is filled into a                                       multidose powder inhaler. Each dose contains                                  Steroid, micronized           0.1     mg                                      Lactose, micronized           1       mg                                      Formulation 13, capsule for treating                                          the small bowel                                                               Steroid                       1.0     mg                                      Sugar spheres                 321     mg                                      Aquacoat ECD 30               6.6     mg                                      Acetyltributyl citrate        0.5     mg                                      Polysorbate 80                0.1     mg                                      Eudragit L100-55              17.5    mg                                      Triethylcitrate               1.8     mg                                      Talc                          8.8     mg                                      Antifoam MMS                  0.01    mg                                      Formulation 14, capsule for treating                                          the large bowel                                                               Steroid                       2.0     mg                                      Sugar spheres                 305     mg                                      Aquacoat ECD 30               5.0     mg                                      Acetyltributyl citrate        0.4     mg                                      Polysorbate 80                0.14    mg                                      Eudragit NE30 D               12.6    mg                                      Eudragit S100                 12.6    mg                                      Talc                          12.6    mg                                      Formulation 15, rectal enema                                                  Steroid                       0.02    mg                                      Sodium carboxymethylcellulose 25      mg                                      Disodium edetate              0.5     mg                                      Methyl parahydroxybenzoate    0.8     mg                                      Propyl pharahydroxybenzoate   0.2     mg                                      Sodium chloride               7.0     mg                                      Citric acid anhydrous         1.8     mg                                      Polysorbate 80                0.01    mg                                      Water, purified         ad    1.0     ml                                      ______________________________________                                    

Formulation 16, formulation containing liposomebound steroid

A. Preparation of a formulation for instillation

Synthetic dipalmitoylphosphatidylcholine (45 mg),dimyristoylphosphatidylcholine (7 mg), dipalmitoylphosphatidylglycerol(1 mg) and(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione(5 mg) are mixed in a glass tube. All components are dissolved inchloroform. Most of the solvent is evaporated by the use of N₂ and thenunder reduced pressure, which forms a thin film of the lipid componentson the surface of the glass tube. An aqueous solution (0.9% NaCl) isadded to the lipids. Formation of the liposomes is performed at atemperature above the phase transition temperature of the lipids. Theliposomes are formed by shaking or sonication of the solution with theprobe of a sonicator. The resulting suspension contains liposomesranging from very small vesicles to 2 μm in size.

B. Preparation of a formulation for inhalation

The preparation of the liposomes is performed according to Example A,where the aqueous solution contains 10% lactose. The ratio betweenlactose and lipid is 7:3. The liposome suspension is frozen on dry iceand lyophilized. The dry product is micronized resulting in particleswith a mass mean aerodynamic diameter (MMAD) of about 2 μm.

Pharmacology

The selectivity for local antiinflammatory activity can be exemplifiedby the following airway model.

A considerable fraction of inhaled GCS is deposited in the pharynx andis subsequently swallowed ending up in the gut. This fractioncontributes to the unwanted side effects of the steroid since it isacting outside the area intended for treatment (the lung). Therefore, itis favourable to use a GCS with high local anti-inflammatory activity inthe lung but low GCS induced effects after oral administration. Studieswere therefore done in order to determine the GCS induced effects afterlocal application in the lung as well as after per oral administrationand the differentiation between glucocorticosteroid actions in thetreated lung region and outside this area were tested in the followingway.

Test models

A) Test model for desired local antiinflammatory activity on airwaymucosa (left lung lobe).

Sprague Dawley rats (250 g) were slightly anaesthetized with Ephrane andthe glucocorticosteroid test preparation (in liposomes suspended insaline) in a volume of 0.5 ml/kg was instilled into just the left lunglobe. Two hours later a suspension of Sephadex (5 mg/kg in a volume of 1ml/kg) was instilled in the trachea well above the bifurcation so thatthe suspension reached both the left and right lung lobes. Twenty hourslater the rats were killed and the left lung lobes dissected out andweighed. Control groups got vehicle instead of glucocorticosteroidpreparation and saline instead of Sephadex suspension to determine theweight of non-drug treated Sephadex edema and the normal lung weight.

B) Test model for unwanted systemic effect by orally absorbedglucocorticosteroid

Sprague Dawley rats (250 g) were slightly anaesthetized with Ephrane andthe GCS test preparation in a volume of 1.0 ml/kg was given orally. Twohours later a suspension of Sephadex (5 mg/kg in a volume of 1 ml/kg)was instilled in the trachea well above the bifurcation so that thesuspension reached both the left and the right lung lobes. Twenty hourslater, the rats were killed and the lung lobes were weighed. Controlgroups got vehicle instead of glucocorticosteroid preparation and salineinstead of Sephadex suspension to determine the weight of non-drugtreated Sephadex edema and the normal weight.

The results of the comparative study are given in Table 1. Thepharmacologic profile of the compounds of the invention was compared tothose of budesonide-21-palmitate and flumethasone-21-palmitate inliposomes. All steroids of the invention show higher localanti-inflammatory potency in the lung after local application thanbudesonide-21-palmitate in liposomes. Furthermore, the results alsodemonstrate a higher lung selectivity of the tested compounds of theinvention compared to the selected prior art compounds, since the doserequired to inhibit lung edema (ED₅₀) by oral administration of theabove mentioned compounds are 158 (example 3), 247 (example 7) and 559(example 1) times higher and of budesonide-21-palmitate 66 times higherand of flumethasone-21-palmitate 8 times higher than the dose needed toinhibit lung edema by local application to the lung of the drugs.

Thus it can be concluded that the compounds of the invention are wellsuited for local treatment of inflammatory disorders in the skin andvarious cavities of the body (e.g. lung, nose, bowel and joint).

                  TABLE 1                                                         ______________________________________                                        Effects of tested glucocorticosteroids in liposomes in the                    Sephadex induced lung edema model in the rat. The results are                 given in relation to the corresponding                                        control group given Sephadex.                                                            ED.sub.50 (left                                                    Compound   lung admini- ED.sub.50 (p.o.                                                                         Ratio                                       according to                                                                             stration; nmol/kg)                                                                         adm. nmol/                                                                              oral/local                                  example    Left lung lobe.sup.x)                                                                      kg) lung.sup.x)                                                                         administration                              ______________________________________                                        Budesonide-21-                                                                           23           1520       66                                         palmitate (RS)                                                                Flumethasone-21-                                                                         2.2           18        8                                          palmitate                                                                     7          2.3          568       247                                         6          1.8          --                                                    3          3.5          554       158                                         1          1.5          839       559                                         ______________________________________                                         .sup.x) ED.sub.50 = required glucocorticosteroid dose to reduce the edema     by 50%.                                                                  

We claim:
 1. The compound having the formula ##STR11##
 2. Apharmaceutical composition comprising as active ingredient, the compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 3. Apharmaceutical composition comprising liposomes containing thepharmacologically active compound according to claim 1 and apharmaceutically acceptable carrier.
 4. A pharmaceutical compositionaccording to claim 2 or 3 in dosage unit form.
 5. A method for thetreatment of inflammatory and allergic conditions in mammals whichcomprises administering to a mammal in need of such treatment aneffective amount of the compound according to claim 1.